Integrative approaches to understand systemic lupus erythematosus etiology in trans-ancestry genetic studies

摘要 系统性红斑狼疮(SLE)是一种遗传性自身免疫性疾病，主要影响年轻女性。 系统性红斑狼疮的症状可能非常不同，这给早期诊断带来了巨大的挑战。在其先进的 SLE分期，可导致多器官衰竭，甚至致死。早期诊断是控制和控制疾病的关键 缓解症状，提高生活质量。迄今为止系统性红斑狼疮的全基因组相关性研究 已经确定了&gt；150个基因座。然而，对于大多数基因座来说，因果变异仍然难以捉摸。有很大的兴趣去整合 来自不同人类群体的数据集，以进一步增强发现能力，改进因果变异，并改进 风险预测的准确性。在这项提案中，我们寻求汇总来自 无数的自身免疫性疾病。我们将开发改进的荟萃分析方法，有效地整合 来自多个性状和祖先的数据。我们还将开发更好的精细制图方法，可以将 统计方法和实验验证。最后，我们将开发出更准确的遗传风险评分 使用来自多个祖先和特征的数据集，并将它们与常用的实验室值相结合 改进了疾病风险预测。我们将发布实现这些方法的有用软件包，以 有益于其他特征的研究，并最大限度地发挥拟议研究的影响。

ABSTRACT Systemic lupus erythematosus (SLE) is a heritable autoimmune disease that primarily affects young females. SLE symptoms can be very heterogeneous, which posts great challenges in early diagnosis. In its advanced stages, SLE can lead to multiple organ failures and even fatality. Early diagnosis is critical for controlling and mitigating the symptoms and improving the quality of life. Genome-wide association studies of SLE to date have identified >150 loci. Yet, the causal variants remain elusive for most loci. There is great interest to integrate datasets from diverse human populations to further empower discovery, refine causal variants, and improve the risk prediction accuracy. In this proposal, we seek to aggregate available GWAS summary statistics from a myriad of autoimmune diseases. We will develop improved meta-analysis methods that effectively integrate data from multiple traits and ancestries. We will also develop better fine-mapping methods that can integrate statistical approaches and experimental validations. Finally, we will develop more accurate genetic risk scores using datasets from multiple ancestries and traits, and combine them with commonly used lab values for improved disease risk predictions. We will release useful software packages implementing these methods to benefit studies of other traits and maximize the impact of the proposed research.